Estrogen synthetase inhibitors. 2. Comparison of the in vitro aromatase inhibitory activity for a variety of nitrogen heterocycles substituted with diarylmethane or diarylmethanol groups.
The preparation and in vitro aromatase inhibitory activity of a wide variety of heterocyclic (4,4'-dichlorodiphenyl)methanes and -methanols are described. The choice of the two diaryl-bearing moieties as a vehicle for the evaluation of the heterocycles was made by the comparison of series of imidazole and pyridine-derived compounds with similar pyrimidine compounds reported previously. A structural model for the most active compounds is also presented. The activity of a related series of the compounds which contain two heterocyclic moieties was found to be consistent with the model. Many of the compounds evaluated, including representatives of the pyridine, imidazole, pyrimidine, pyrazole, triazole, thiazole, and isothiazole classes, exhibit EC50 potencies for aromatase inhibition at low nanomolar levels. These compounds are at least as potent as other nonsteroidal aromatase inhibitors reported previously.
Jones
C D
CD
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285.
Winter
M A
MA
Hirsch
K S
KS
Stamm
N
N
Taylor
H M
HM
Holden
H E
HE
Davenport
J D
JD
Krumkalns
E V
EV
Suhr
R G
RG
D000735:Androstenedione / Q000378:metabolism; D000818:Animals; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors; D001559:Benzhydryl Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D055598:Chemical Phenomena; D002621:Chemistry; D005260:Female; D006064:Gonadotropins, Equine / Q000494:pharmacology; D007093:Imidazoles; D008861:Microsomes / Q000201:enzymology; D015394:Molecular Structure; D009249:NADP / Q000378:metabolism; D010053:Ovary / Q000201:enzymology / Q000648:ultrastructure; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013844:Thiazoles; D014230:Triazoles; D014961:X-Ray Diffraction
D047072:Aromatase Inhibitors; D001559:Benzhydryl Compounds; D006064:Gonadotropins, Equine; D007093:Imidazoles; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D013844:Thiazoles; D014230:Triazoles; D000735:Androstenedione; D009249:NADP; D001141:Aromatase